TY - JOUR T1 - A TOXICOLOGICAL STUDY OF SUCCINYL SULFATHIAZOLE JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 231 LP - 246 VL - 75 IS - 3 AU - A. D. WELCH AU - PAUL A. MATTIS AU - ALBERT R. LATVEN Y1 - 1942/07/01 UR - http://jpet.aspetjournals.org/content/75/3/231.abstract N2 - Succinyl sulfathiazole, 2-(N4-succinyl-sulfanilamido)-thiazole, a new sulfonamide of promise as an intestinal bacteriostatic agent, has been studied from the standpoint of acute and chronic toxicity. Absorption of the drug from the gastro-intestinal tract has been shown to be very limited. No toxic effects were observed in mice following oral doses of 40 grams per kgm. Two hours after such doses blood concentrations of 2.6 mgm.% sulfathiazole and 4.2 mgm.% succinyl sulfathiazole were produced. Rats exhibited no depression of the growth rate and no other manifestations of toxicity when fed for 33 days on a chow containing 5% succinyl sulfathiazole. The mean blood concentrations found were 1.4 mgm.% sulfathiazole and 4.6 mgm.% succinyl sulfathiazole. Monkeys were given a solution of sodium succinyl sulfathiazole by stomach tube every 4 hours for 30 days in dosages up to 5.0 grams per kgm. per day. All animals gained weight and no toxic effects were seen; microscopic examinations of the tissues revealed no abnormalities. The average blood concentrations on the maximum dosage were 0.8 mgm.% sulfathiazole and 3.0 mgm.% succinyl sulfathiazole; calculations based on the maximum concentration found in the urine indicated that less than 4% of the ingested dosage (5 grams per kgm.) was excreted by the kidneys. The effects of parenteral administration of succinyl sulfathiazole were studied to disclose any toxicity which might be caused by high blood and urine concentrations, should these occur under unpredictable circumstances following oral administration. By various parenteral routes one gram per kgm. (in the form of a neutral 25% solution of the sodium salt) was given to unilaterally nephrectomized monkeys daily for 10 days. The greater the local damage at the sites of the injections, the more significant was the decrease in hemoglobin concentration and erythrocyte count; these changes were not seen in all monkeys. Moderate activity of the bone-marrow was apparently compensatory to the decrease in blood constituents. Increased vascularity of the glomeruli of the kidney was ascribed to the high concentrations of drug in the blood and glomerular filtrate. In the blood, concentrations up to 170 mgm.% were reached (following intravenous injection); and in the urine a maximum concentration of 12 grams per 100 cc. was found (following intramuscular injection). Crystal formation in the urine, which occurred irregularly, was apparently related primarily to urinary pH; no blockage of the urinary tract occurred and no crystals were found at autopsy. Injected intraperitoneally in mice as an olive oil suspension, succinyl sulfathiazole had an approximate LD50 of 5.7 grams per kgm. Blood concentrations two hours following the administration of the LD40 dose of drug were 8.2 mgm.% sulfathiazole and 263 mgm.% succinyl sulfathiazole. Injected intraperitoneally as an aqueous solution of the sodium salt, the LD50 was found to be approximately 7.5 grams per kgm.; 7.0 grams per kgm. (the approximate LD40) produced a blood concentration of 9.7 mgm.% sulfathiazole and 775 mgm.% succinyl sulfathiazole, 30 minutes following drug administration. All evidence available at present indicates that toxic reactions of consequence will not occur following the oral administration of succinyl sulfathiazole. ER -